IL-13 is a globular protein containing four α-helices belonging to the family of growth hormone-like cytokines which includes IL-4, granulocyte macrophage-colony-stimulating factor, IL-2, and macrophage-colony-stimulating factor. IL-13 binds to a heterodimeric receptor composed of IL-13Rα1, a 52-kDa subunit, and p140, a 140 kDa subunit, resulting in activation of STAT6. A second IL-13 receptor, Ra2, is also known to exist. The Ra1 receptor is responsible for initiating the signaling cascade upon binding with IL-13. The Ra2 receptor binds to IL-13 with greater affinity than Ra1 however its function has yet to be determined.
Patients experiencing an asthmatic response have an increase of activated CD4+ Th2 lymphocytes that cause inflammation of the airways. Activated Th2 lymphocytes secrete cytokines (IL-4, IL-5, IL-9, IL-10 and IL-13) that stimulate inflammation causing tissue damage associated with airway hyper-reactivity. IL-13 has been shown to be a major contributing factor of asthma in murine models and the human IL-13 variant of a single nucleotide polymorphism, R130Q (Graves, et al., 2000 J Allergy Clin Immunol 105: 506-13) was shown to be a significant risk factor for asthma development (Heinzmann et al., 2000 Hum. Mol. Genet. 9:549-559; Am. J. Respir.; Howard et al., 2001 Cell Mol. Biol. 25:377-384; WO0123410). Treatment with an anti-IL-13 neutralizing Mab in a murine model inhibited an asthmatic response in stimulated animals. Thus, evidence indicates that neutralizing IL-13 could be beneficial in treating asthma and airway constriction in patients.
Accordingly, there is a need to provide human antibodies specific for human IL-13 for use in therapy to diminish or eliminate IL-13-mediated diseases, as well as improvements over known antibodies or fragments thereof.